Expert Critique

Patients with newly diagnosed advanced non-small cell lung cancer (NSCLC) must have a thorough understanding of their disease course with or without further medical intervention. However, evidence from a survey-based study of primary care physicians in 2007 and a review of advanced NSCLC patients in the SEER-Medicare database suggest that many patients with newly diagnosed metastatic NSCLC may not be receiving appropriate National Comprehensive Cancer Network guideline therapy or referred to the appropriate specialists (i.e., medical oncologist, radiation oncologist, surgeon). This may be due to primary care physicians’ underestimation of the new, relatively effective therapies for advanced NSCLC and lack of appreciation for the especially poor survival of patients with NSCLC without any medical interventions. However, as data from the National Cancer Data Base over the time period of 1998 to 2012 demonstrate, untreated patients with Stages IIIA and IV NSCLC have reduced survival when compared with their treated peers, yet more patients with advanced disease appear to be untreated over this time period. While data from 2012 onwards are not available, the studies above reaffirm the importance of a detailed physician-patient conversation about the risks and benefits of treatment, including the natural course of the disease with or without therapy, as well as considerations of other factors, including health-related quality of life, and treatment side effects.,br />

Full Critique

Lung cancer specialists and their patients seem to be in a bit of a Goldilocks situation. The tremendous advances made in personalized medicine have allowed for patients to receive treatments that are "just right" for them.

Then there is the problem of a complete lack of treatment. A recent study from the University of California Davis (UCD) found that despite decades worth of progress in diagnosis and treatment, some advanced-stage lung cancer patients are still left behind.

Elizabeth David, MD, of the section of general thoracic surgery and outcomes research group at UCD, explained in an interview that she came upon this trend when she and her colleagues evaluated the California Cancer Registry. They reported that among stage IIIA non-small cell lung cancer (NSCLC) patients, there were "increased numbers of patients being untreated between 2004 and 2012 (0.9%, P<0.001). Additionally, among stage IIIA, IIIB, and IV patients, there was a trend of significantly decreased use of multimodality regimens in the California Cancer Registry."

The results of the study "prompted us to look at the national-level data, and we were surprised to see the rates of receiving no treatment increasing," David said.

Study Details

She acknowledged that the California study, and the newer look at the National Cancer Data Base (NCDB), had data only through 2012, "which was right at the cusp of the targeted therapy era -- I hope that when we have follow-up studies, we'll see that trend changing."

Nevertheless, the trend exists and needs to be addressed, she and her colleagues wrote. They looked at NCDB for cases of biopsy-proven NSCLC from 1998 to 2012, and used propensity matching to identify patients who did not receive treatment who were not different from patients who underwent standard-of-care therapies.

"The unknown treatment group included patients with missing data for chemotherapy, surgery, or radiation, whereas the no-treatment group included patients who did not have an operation, radiation, or chemotherapy," the team explained.

For stages IIIA and IV, the proportion of untreated patients increased over the 14-year study period by 0.21% (P=0.003) and 0.4% (P<0.0001), while for stage IIIB there was no significant change in the proportion of untreated patients. In comparison, the proportion of untreated stage I patients decreased by 0.66% (P<0.0001) and stage II, by 0.23% (P=0.022).

Looking at the factors associated with overall survival (OS) and not receiving treatment, the researchers found that a host of reasons, including the type of treatment, age, sex, race, insurance status, clinical stage, tumor size, and type of treatment facility were all signiﬁcantly associated with OS (P<0.0001).

Using propensity matching, David and colleagues identified approximately 6,000 matched pairs of patients with stage IIIA disease and over 19,000 matched pairs of patients with stage IV disease, and noted significant differences in OS between the matched pairs. For stage IIIA disease, the median OS was 16.5 versus 6.1 months, and for stage IV, median OS was 9.3 versus 2 months (P<0.0001 for both).

For stages IIIA and IV, the proportion of untreated patients increased over the 14-year study period by 0.21% (P=0.003) and 0.4% (P<0.0001), while for stage IIIB there was no significant change in the proportion of untreated patients. In comparison, the proportion of untreated stage I patients decreased by 0.66% (P<0.0001) and stage II by 0.23% (P=0.022).

'Better Than No Treatment'

So what is the take-home message from the study? "It's important that patients understand that when they are quoted statistics about survival, there are a high percentage of untreated patients in those statistics who are bringing the numbers down," David explained. "I think the big take-home message is that any treatment at all is better than no treatment."

Imparting this message to patients is going to require that all of the relevant healthcare players do their part, starting with primary care providers, she said. Unfortunately, however, the line of communication between the first-line physicians and patients is not always clear.

A survey-based study by Joan Schiller, MD, then at the University of Texas Southwestern Medical Center in Dallas, and colleagues showed that primary care physicians were less likely to refer patients with advanced lung cancer than patients with advanced breast cancer for cancer treatment. When advanced lung cancer patients were referred, it was often only for symptom control. Also, more physicians knew that chemotherapy increased survival in advanced breast cancer than in advanced lung cancer -- "Yet, when asked directly, physicians stated that the type of cancer was not a factor in their decisions to refer patients."

One caveat: The study by Schiller's group was done in 2007, so again, it was before the explosion of targeted therapies. But a later study from 2013 demonstrated that, among 28,977 advanced-stage NSCLC patients from the SEER database, younger age, white race, higher income, and primary physician specialty, other than family practice, predicted a higher likelihood of referrals to medical oncologists.

The authors also found that seeing the three types of cancer specialists (medical oncologists, radiation oncologists, and surgeons) led to a higher likelihood of patients receiving guidelines-based therapies, depending on the disease stage (compared with seeing a medical oncologist only):

Stage IIIA: odds ratio 20.6 (P<0.001)

Stage IIIB: OR 77.2 (P<0.001)

Stage IV: OR 1.2 (P<0.011)

"Our study suggests that most patients (84%) will see at least a medical oncologist, whereas 31% will see all cancer specialists," wrote Bernardo Goulart, MD, of Fred Hutchinson Cancer Research Center in Seattle, and colleagues. "Patients who saw a medical oncologist, a radiation oncologist, and a surgeon had the highest likelihood of receiving treatments endorsed by the National Comprehensive Cancer Network guidelines, a ﬁnding that was particularly relevant in patients with stage III NSCLC."

On the other hand, patients who were older, black, or lived in economically challenged areas were less likely to be referred to medical oncologists, and patients initially seen by family practice physicians were less likely to see medical oncologists.

"These ﬁndings indicate that sociodemographic characteristics still represent access barriers to specialty care for NSCLC and that some general practitioners are not fully aware of the role of chemotherapy for stages III and IV NSCLC," Goulart's group concluded.

Education Tools

What can lung cancer specialists do to increase awareness of treatment options among their primary care colleagues and patients? Education is key, but figuring out how to maximize that education may require working backwards to some extent.

David said that her group is already exploring the question of treatment awareness: "We are starting to look into this ... right now, we are focusing on the lung cancer care providers. We are looking at how treatment decisions are made -- how does physician perception, knowledge, and bias influence the decision-making process. Then we'll use this data to build education tools if we find they are needed."

In the meantime, David stressed that all specialists in cancer care -- primary care doctors, oncologists, palliative and supportive care specialists, and even patients -- understand how far therapies for advanced lung cancer have come, and be "aware that all of the new therapies are easier to tolerate than they used to be. Surgery is easier to recover from; radiation can be given faster than it used to be; and targeted therapies are easier for patients to tolerate.

"I think that's important to get across to patients because they are weighing treatment options along with quality-of-life issues," she added.

While the reasons for lack of treatment are complex, there is a more straightforward reality that is harder to deny -- mortality is higher in patients with untreated lung cancer. A 2013 meta-analysis concluded that untreated lung cancer patients lived on average for 7.15 months (95% CI 5.87-8.42).

"Comprehensive data on the natural history of lung cancer is required for informed decision-making by patients and physicians. For patients, it serves as the basis for their expected outcome with and without treatment, which is critical in cases of diseases with high mortality," wrote Ambuj Kumar, MD, MPH, of the University of South Florida Clinical and Translational Science Institute in Tampa, and colleagues. "For physicians, accurate and reliable information facilitates shared decision-making with patients, related to choice of interventions or no intervention."

The study by Schiller's group was funded by the American Medical Association.

David and co-authors disclosed no relevant relationships with industry.

The study by Goulart's group was supported by Genentech. Goulart and co-authors disclosed relevant relationships with Genentech and Roche, and some co-authors are employees of Genentech.

Kumar and co-authors disclosed no relevant relationships with industry. One co-author disclosed support from the U.S. Army Medical Research and Material Command.

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